Tobacco smoking is a leading cause of premature death. Nicotine, the primary active alkaloid in tobacco, is generally accepted as being responsible for maintaining smoking behavior. As well, chronic use of addictive drugs has been found to produce enduring neuroadaptations in the corticostriatal brain circuitry involved in the plasticity of learning and behavior. Existing evidence suggests that a disruption in glutamate homeostasis (a balance between extrasynaptic and synaptic neuronal glutamate concentrations that regulate synaptic plasticity) within the NA is a contributing mechanism to this chronic relapse vulnerability. It is thought that dynamic drug-induced changes in this pathway impair the normal processing of information that contributes to the adaptive regulation of motivated behavior. It is unclear, however, to what extent nicotine self-administration and the reinstatement of nicotine-seeking behavior causes alterations in glutamate homeostasis. I am proposing to use an animal model of nicotine-seeking to determine if changes in glutamate homeostasis during nicotine withdrawal and reinstated nicotine-seeking are similar to those that occur during cocaine withdrawal and cocaine-seeking. Specifically, I hypothesize that nicotine self-administration will change protein levels associated with glutamate homeostasis, as well as synaptic release of NA glutamate and dopamine during cue-induced reinstatement. The proposed research will determine the relationship, if any, between nicotine and cocaine on alterations in glutamate homeostasis as an underlying neurobiological mechanism of relapse to different drugs of abuse. As well, the proposed research has the potential to reveal novel mechanisms of nicotine addiction, and thus may aid in targeting more effective pharmacological treatment. In the process, I will be trained in Western blot analysis, in vivo microdialysis involving no-net flux following nicotine self-administration and extinction training, as well as cu-induced reinstatement of nicotine-seeking behavior in rats. PUBLIC HEALTH RELEVANCE: Drug addiction is associated with long-lasting brain changes that cause heightened relapse vulnerability, even after extended drug abstinence. The proposed research has the potential to reveal novel neurobiological mechanisms of nicotine addiction, and could contribute to the development of novel therapeutic options aimed at reversing nicotine- induced alterations.